Phosphorylation-induced changes in the PDZ domain of Dishevelled 3

Abstract

The PDZ domain of Dishevelled 3 protein belongs to a highly abundant protein recognition motif which typically binds short C-terminal peptides. The affinity of the PDZ towards the peptides could be fine-tuned by a variety of post-translation modifications including phosphorylation. However, how phosphorylations affect the PDZ structure and its interactions with ligands remains elusive. Combining molecular dynamics simulations, NMR titration, and biological experiments, we explored the role of previously reported phosphorylation sites and their mimetics in the Dishevelled PDZ domain. Our observations suggest three major roles for phosphorylations: (1) acting as an on/off PDZ binding switch, (2) allosterically affecting the binding groove, and (3) influencing the secondary binding site. Our simulations indicated that mimetics had similar but weaker effects, and the effects of distinct sites were non-additive. This study provides insight into the Dishevelled regulation by PDZ phosphorylation. Furthermore, the observed effects could be used to elucidate the regulation mechanisms in other PDZ domains.

Wnt4 and ephrinB2 instruct apical constriction via Dishevelled and non-canonical signaling

“…To further test our hypothesis, we employed a Dsh2-S267E mutant. A previous study demonstrated that Dsh3 also has an interaction between the C-terminal PBM (PDZ-binding motif) and its own PDZ domain 54 . This interaction can be regulated by post-translational modifications including phosphorylation.…”

“…This interaction can be regulated by post-translational modifications including phosphorylation. Interestingly, the point mutation (Serine 263 to Glutamic acid) suppressed the intramolecular interaction of the PDZ domain and the C-terminal motif resulting in the open conformation of Dsh3 54 . Since Dsh2 and 3 have a highly conserved PDZ domain and PBM, we made the same single amino acid mutation (S267E) in Dsh2 to test whether the open conformation of Dsh2 is more efficient at interacting with WERDS components.…”

Dishevelled localization and function are differentially regulated by structurally distinct sterols

“…Also, supramolecular intracellular condensates of DVL2 colocalize with centrosomal proteins such as γ-globulin and CEP164 in a Wnt-dependent and cell cycle-dependent manner (Schubert et al, 2022). Lastly, post-translational modification of DVL residues through acetylation or phosphorylation can also regulate DVL nuclear accumulation (Sharma et al, 2019), as well as DVL protein-protein interactions through PDZ domain activity (Jurasek et al, 2021). A previous study linked DVL3 phosphorylation patterns to its function (Hanáková et al, 2019).…”